Leukodystrophies are a heterogeneous group of genetic disorders affecting the white matter of the central nervous system and sometimes with peripheral nervous system involvement. There are over 40 different leukodystrophies, with an overall population incidence of 1 in 7663 live births. They are now most commonly grouped based on the initial pattern of central nervous system white matter abnormalities on neuroimaging. All leukodystrophies have MRI hyperintense white matter on T2-weighted images, whereas T1 signal may be variable. Mildly hypo-, iso-, or hyperintense T1 signal relative to the cortex suggests a hypomyelinating pattern. A significantly hypointense T1 signal is more often associated with demyelination or other pathologies. Recognition of the abnormal MRI pattern in leukodystrophies greatly facilitates its diagnosis. Early diagnosis is important for genetic counseling and appropriate therapy where available.
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• Leukodystrophies are classically defined as progressive genetic disorders that primarily and predominantly affect the white matter of the brain.
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• The pattern of abnormalities on brain MRI, and sometimes brain CT, is the most useful diagnostic tool.
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• Radial diffusivity on brain diffusion weighted imaging correlates with motor handicap.
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• X-linked adrenoleukodystrophy is the most common leukodystrophy and has effective therapy if applied early in the disease course.
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• Lentiviral hemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy shows promise.
Historical note and terminology
The first leukodystrophies were identified early last century. Both Nissl and Alzheimer coincidentally reported metachromatic staining of the white matter of an adult patient with what we would now call metachromatic leukodystrophy (04; 45). Globoid cell leukodystrophy, or Krabbe disease, was described in 1916. Hallervorden suggested that these globoid cells may contain kerasin or cerebroside. Biochemical and histochemical studies confirmed the presence of cerebroside in globoid cells (06), and galactocerebroside was the only glycolipid that could produce globoid cells when injected into the central nervous system of experimental animals. Jatzkewitz and Austin independently identified the metachromatic substance as sulfatide, a sulfated glycolipid (32; 06). Subsequently, Austin and colleagues and Mehl and Jatzkewitz showed that the sulfatide accumulation was caused by reduced activity of arylsulfatase A, the lysosomal enzyme that hydrolyzes galactose-3-sulfate from sulfatides (05; 42). Until the early 1990s, the known leukodystrophies were metachromatic leukodystrophy, Krabbe disease, Canavan disease, Alexander disease, adrenoleukodystrophy, Pelizaeus-Merzbacher disease, and 2 forms of adult-onset autosomal dominant leukodystrophies (02). As of 1994, a series of new leukodystrophy syndromes have been described (Schiffmann et al 1994; 33). Typically, the etiology of the leukodystrophy syndromes is discovered a few years after their initial clinical description.
One difficulty has been in deciding which clinical syndrome qualifies as a leukodystrophy and which is just a leukoencephalopathy or a disorder associated with white matter abnormalities on imaging or on pathological examination. The term leukoencephalopathy has been applied to both heritable and acquired disorders, such as toxic, acquired vascular, or infectious. There were a number of attempts to identify a list of leukodystrophies, and the most recent was done by consensus of physician experts in the field (Table 1) (69). Leukodystrophies do not include disorders characterized as heritable leukoencephalopathies (Table 2) or acquired CNS myelin disorders, such as multiple sclerosis and related acquired demyelinating processes, infectious and post-infectious white matter damage, toxic injuries and non-genetic vascular insults (66).